Article
Local HSV-TK suicide gene therapy in the orthotopic U87 glioblastoma model using human bone-marrow derived mesenchymal stem cells
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Authors
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Lasse Dührsen
- Department of Neurosurgery , University Medical Center Hamburg-Eppendorf, Hamburg, Deutschland
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Sophie Montag
- Hans Dietrich Hermann Labor für Hirntumorbiologie, University Medical Center Hamburg-Eppendorf, Hamburg, Deutschland
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Svenja Zapf
- Hans Dietrich Hermann Labor für Hirntumorbiologie, University Medical Center Hamburg-Eppendorf, Hamburg, Deutschland
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Daniela Hirsch
- Apceth, Munich, Deutschland
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Jan Sedlacik
- Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neuroradiologische Diagnostik, Hamburg, Deutschland
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Manfred Westphal
- Universitätsklinikum Hamburg-Eppendorf, Klinik und Poliklinik für Neurochirurgie, Hamburg, Deutschland
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Felix Hermann
- Apceth, Munich, Deutschland
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Nils Ole Schmidt
- University hospital Hamburg-Eppendorf, Klinik und Poliklinik für Neurochirurgie, Neurosurgery, Hamburg, Deutschland
| Published: | June 9, 2017 |
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Outline
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Objective: Mesenchymal stem cells (MSC) show an inherent brain tumor cell tropism that can be exploited for targeted delivery of therapeutic genes to invasive gliomas. Here, we describe the dynamics of human MSC migration and demonstrate that the injection of tumor-targeting MSC is able to deliver a suicide gene to intracerebral growing human glioblastoma xenografts.
Methods: Human MSC from healthy donors were genetically modified to stably express the herpes simplex virus thymidine kinase (TK). The biological activity of MSC and MSC-mediated TK/ganciclovir (GCV) system was assessed in cell migration, survival and bystander assays. The dynamics of Fe- and DiI-labeled MSC migration in time and distribution were tested in the intracranial U87 human glioblastoma model in nude mice and analyses were performed by histology and 7T MR imaging. Therapeutic effects of intratumoral (0.4x106 cells) application was tested likewise. Control groups received either NaCl instead of GCV or MSC containing the empty vector (MSC-control). Therapeutic efficiency was determined by assessment of tumor size by 7T MR-imaging at day 20 and by establishment of Kaplan-Meier survival curves (n=30).
Results: MSCs showed a high tumor tropism with 4.9 times more MSCs migrating towards U87 compared to controls. The MSCs were mainly detected at the peritumoral border compared to the intratumoral distribution and showed an early peak accumulation after 48 hours. Cell survival and bystander assays using different glioma cell lines confirmed the GCV catalytic activity of MSC expressed TK in a GCV dose dependent manner and a significant bystander effect. Intratumoral application of MSC-TK followed by systemic prodrug application of GCV lead to a significant tumor growth inhibition of 86% versus the control groups (p<0.05) which translated in a significant prolonged survival time (p<0.05).
Conclusion: Our data demonstrates that MSC show a rapid targeted migration to intracerebral glioma and accumulate predominately peritumorally within in short time. We demonstrate that these genetically modified human MSC generated under GCP conform conditions are able to target and provide a significant growth inhibtion in a glioma mouse model. Our data support the concept of an autologous stem cell-based therapy for glioblastoma using bone marrow derived MSC.
